Evidence that the novel receptor FGFRL1 signals indirectly via FGFR1

Fibroblast growth factor (FGF) receptor-like protein 1 (FGFRL1) is a recently discovered member of the FGF receptor (FGFR) family. Similar to the classical FGFRs, it contains three extracellular immunoglobulin-like domains and interacts with FGF ligands. However, in contrast to the classical receptors, it does not contain any intracellular tyrosine kinase domain and consequently cannot signal by transphosphorylation. In mouse kidneys, FgfrL1 is expressed primarily at embryonic stages E14-E15 in regions where nascent nephrons develop. In this study, we used whole-mount in situ hybridization to show the spatial pattern of five different Fgfrs in the developing mouse kidney. We compared the expression pattern of FgfrL1 with that of other Fgfrs. The expression pattern of FgfrL1 closely resembled that of Fgfr1, but clearly differed from that of Fgfr2‑Fgfr4. It is therefore conceivable that FgfrL1 signals indirectly via Fgfr1. The mechanisms by which FgfrL1 affects the activity of Fgfr1 remain to be elucidated.

The Science of Exoplanets and Their Systems

A scientific forum on “The Future Science of Exoplanets and Their Systems,” sponsored by Europlanet* and the International Space Science Institute (ISSI)† and co-organized by the Center for Space and Habitability (CSH)‡ of the University of Bern, was held during December 5 and 6, 2012, in Bern, Switzerland. It gathered 24 well-known specialists in exoplanetary, Solar System, and stellar science to discuss the future of the fast-expanding field of exoplanetary research, which now has nearly 1000 objects to analyze and compare and will develop even more quickly over the coming years. The forum discussions included a review of current observational knowledge, efforts for exoplanetary atmosphere characterization and their formation, water formation, atmospheric evolution, habitability aspects, and our understanding of how exoplanets interact with their stellar and galactic environment throughout their history. Several important and timely research areas of focus for further research efforts in the field were identified by the forum participants. These scientific topics are related to the origin and formation of water and its delivery to planetary bodies and the role of the disk in relation to planet formation, including constraints from observations as well as star-planet interaction processes and their consequences for atmosphere-magnetosphere environments, evolution, and habitability. The relevance of these research areas is outlined in this report, and possible themes for future ISSI workshops are identified that may be proposed by the international research community over the coming 2–3 years.

Polonofilizm i polskość wśród czeskich emancypantek w drugiej połowie XIX wieku: przykład Karoliny Světlej

The awakening of national consciousness went hand in hand in Bohemia with an anxiety about national disappearance. In this context, the recourse to Pan-Slavism was for the Czechs a way to encourage themselves through the idea of belonging to a great Slavic world, while the Slavic Congress organized in Prague in 1848 was an attempt to realize this ideal. The Congress was a failure from the political point of view, but it did have some socio-cultural repercussions: notably, it served as a pretext for the advancement of women's issues in Bohemia. It is indeed in the wake of the Congress that Honorata z Wiśniowskich Zapová, a Polish women settled in Prague after her marriage to a Czech intellectual, founded, under the guise of collaboration between all Slavic women, the first women's association, as well as a (very short-lived) Czech-Polish institute, where Czech, as well as Polish girls, could get a quality education in their mother tongue. Honorata was undoubtedly the source of the polonophilia wind that seemed to blow over the Czech emancipation movement in the second half of the nineteenth century. In particular, Karolina Světlá showed in her Memoirs a great recognition for Honorata's efforts in matters of emancipation and education, and explicitly took up the challenge launched by the latter in founding another women's association and in inaugurating a school for underprivileged girls. But the tribute Světlá paid to Honorata is even more evident in her literary work, where Poland and the Polish woman (who often wears Honorata's features) play a significant role (see for example her short novel Sisters or her story A Few Days in the Life of a Prague Dandy). Světlá was probably the Czech feminist writer who, in her activities and in her work, relied most strongly on the Polish woman as a model for the Czech woman. However, she wasn't alone. In general, it was a characteristic of the Czech feminist movement of the second half of the nineteenth century to have recourse to the Polish woman and to Poland as a landmark for comparison and as a goal to be achieved.

Should There Be New Multilateral Rules for Digital Trade?

The Internet revolution and the digital environment have spurred a significant amount of innovative activity that has had spillover effects on many sectors of the economy. For a growing group of countries – both developed and developing – digital goods and services have become an important engine of economic growth and a clear priority in their future-oriented economic strategies. Neither the rapid technological developments associated with digitization, nor their increased societal significance have so far been reflected in international economic law in a comprehensive manner. The law of the World Trade Organization (WTO) in particular, has not reacted in any proactive manner. A pertinent question that arises is whether the WTO rules are still useful and able to accommodate the new digital economy or whether they have been rendered outdated and incapable of dealing with this important development? The present think-piece seeks answers to these questions and maps the key issues and challenges which the WTO faces. In appraisal of the current state of affairs, developments in venues other than the WTO, and proposals tabled by stakeholders, some recommendations for the ways forward are made.

Response to LIVint-15-00100

Although AST-to-platelet ratio index (APRI) and FIB-4 have been compared with liver biopsy in patients with hepatitis C virus (HCV), hepatitis B virus (HBV), HIV/HCV co-infection, and HIV/HBV co-infection, Johannessen and Lemoine stress that they have not been validated in HIV mono-infected populations in SSA. However, this is unlikely to occur because liver biopsy does not play a role in HIV management and the procedure carries its own risks for complication. Clinicians using APRI and FIB-4 in this setting should be aware of this limitation and should interpret test results in the context of each patient's clinical scenario. This article is protected by copyright. All rights reserved.

The FgfrL1 receptor is required for development of slow muscle fibers.

FgfrL1, which interacts with Fgf ligands and heparin, is a member of the fibroblast growth factor receptor (Fgfr) family. FgfrL1-deficient mice show two significant alterations when compared to wildtype mice: They die at birth due to a malformed diaphragm and they lack metanephric kidneys. Utilizing gene arrays, qPCR and in situ hybridization we show here that the diaphragm of FgfrL1 knockout animals lacks any slow muscle fibers at E18.5 as indicated by the absence of slow fiber markers Myh7, Myl2 and Myl3. Similar lesions are also found in other skeletal muscles that contain a high proportion of slow fibers at birth, such as the extraocular muscles. In contrast to the slow fibers, fast fibers do not appear to be affected as shown by expression of fast fiber markers Myh3, Myh8, Myl1 and MylPF. At early developmental stages (E10.5, E15.5), FgfrL1-deficient animals express slow fiber genes at normal levels. The loss of slow fibers cannot be attributed to the lack of kidneys, since Wnt4 knockout mice, which also lack metanephric kidneys, show normal expression of Myh7, Myl2 and Myl3. Thus, FgfrL1 is specifically required for embryonic development of slow muscle fibers.

Microscale mapping of alteration conditions and potential biosignatures in basaltic-ultramafic rocks on early Earth and beyond

Subseafloor environments preserved in Archean greenstone belts provide an analogue for investigating potential subsurface habitats on Mars. The c. 3.5-3.4 Ga pillow lava metabasalts of the mid-Archean Barberton greenstone belt, South Africa, have been argued to contain the earliest evidence for microbial subseafloor life. This includes candidate trace fossils in the form of titanite microtextures, and sulfur isotopic signatures of pyrite preserved in metabasaltic glass of the c. 3.472 Ga Hooggenoeg Formation. It has been contended that similar microtextures in altered martian basalts may represent potential extraterrestrial biosignatures of microbe-fluid-rock interaction. But despite numerous studies describing these putative early traces of life, a detailed metamorphic characterization of the microtextures and their host alteration conditions in the ancient pillow lava metabasites is lacking. Here, we present a new nondestructive technique with which to study the in situ metamorphic alteration conditions associated with potential biosignatures in mafic-ultramafic rocks of the Hooggenoeg Formation. Our approach combines quantitative microscale compositional mapping by electron microprobe with inverse thermodynamic modeling to derive low-temperature chlorite crystallization conditions. We found that the titanite microtextures formed under subgreenschist to greenschist facies conditions. Two chlorite temperature groups were identified in the maps surrounding the titanite microtextures and record peak metamorphic conditions at 315 ± 40°C (XFe3+(chlorite) = 25-34%) and lower-temperature chlorite veins/microdomains at T = 210 ± 40°C (lower XFe3+(chlorite) = 40-45%). These results provide the first metamorphic constraints in textural context on the Barberton titanite microtextures and thereby improve our understanding of the local preservation conditions of these potential biosignatures. We suggest that this approach may prove to be an important tool in future studies to assess the biogenicity of these earliest candidate traces of life on Earth. Furthermore, we propose that this mapping approach could also be used to investigate altered mafic-ultramafic extraterrestrial samples containing candidate biosignatures.

T-cell reprogramming through targeted CD4-coreceptor and T-cell receptor expression on maturing thymocytes by latent Circoviridae family member porcine circovirus type 2 cell infections in the thymus

Although porcine circovirus type 2 (PCV2)-associated diseases have been evaluated for known immune evasion strategies, the pathogenicity of these viruses remained concealed for decades. Surprisingly, the same viruses that cause panzootics in livestock are widespread in young, unaffected animals. Recently, evidence has emerged that circovirus-like viruses are also linked to complex diseases in humans, including children. We detected PCV2 genome-carrying cells in fetal pig thymi. To elucidate virus pathogenicity, we developed a new pig infection model by in vivo transfection of recombinant PCV2 and the immunosuppressant cofactor cyclosporine A. Using flow cytometry, immunofluorescence and fluorescence in situ hybridization, we found evidence that PCV2 dictates positive and negative selection of maturing T cells in the thymus. We show for the first time that PCV2-infected cells reside at the corticomedullary junction of the thymus. In diseased animals, we found polyclonal deletion of single positive cells (SPs) that may result from a loss of major histocompatibility complex class-II expression at the corticomedullary junction. The percentage of PCV2 antigen-presenting cells correlated with the degree of viremia and, in turn, the severity of the defect in thymocyte maturation. Moreover, the reversed T-cell receptor/CD4-coreceptor expression dichotomy on thymocytes at the CD4(+)CD8(interm) and CD4SP cell stage is viremia-dependent, resulting in a specific hypo-responsiveness of T-helper cells. We compare our results with the only other better-studied member of Circoviridae, chicken anemia virus. Our data show that PCV2 infection leads to thymocyte selection dysregulation, adding a valuable dimension to our understanding of virus pathogenicity.

1D.03: Inactive Matrix Gla Protein is Assocated with Renal Resistive Index in a Population-Based Study

OBJECTIVE Renal resistive index (RRI) varies directly with renal vascular stiffness and pulse pressure. RRI correlates positively with arteriolosclerosis in damaged kidneys and predicts progressive renal dysfunction. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular (CV) markers, CV outcomes and mortality. In this study we hypothesize that increased RRI is associated with high levels of dp-ucMGP. DESIGN AND METHOD We recruited participants via a multi-center family-based cross-sectional study in Switzerland exploring the role of genes and kidney hemodynamics in blood pressure regulation. Dp-ucMGP was quantified in plasma samples by sandwich ELISA. Renal doppler sonography was performed using a standardized protocol to measure RRIs on 3 segmental arteries in each kidney. The mean of the 6 measures was reported. Multiple regression analysis was performed to estimate associations between RRI and dp-ucMGP adjusting for sex, age, pulse pressure, mean pressure, renal function and other CV risk factors. RESULTS We included 1035 participants in our analyses. Mean values were 0.64 ± 0.06 for RRI and 0.44 ± 0.21 (nmol/L) for dp-ucMGP. RRI was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, pulse pressure, mean pressure, heart rate, renal function, low and high density lipoprotein, smoking status, diabetes, blood pressure and cholesterol lowering drugs, and history of CV disease (P < 0.001). CONCLUSIONS RRI is independently and positively associated with high levels of dp-ucMGP after adjustment for pulse pressure and common CV risk factors. Further studies are needed to determine if vitamin K supplementation can have a positive effect on renal vascular stiffness and kidney function.

Adjustment Disorders Are Uniquely Suited for eHealth Interventions: Concept and Case Study

Background: Adjustment disorders (also known as mental distress in response to a stressor) are among the most frequently diagnosed mental disorders in psychiatry and clinical psychology worldwide. They are also commonly diagnosed in clients engaging in deliberate self-harm and in those consulting general practitioners. However, their reputation in research-oriented mental health remains weak since they are largely underresearched. This may change when the International Statistical Classification of Diseases-11 (ICD-11) by the World Health Organization is introduced, including a new conceptualization of adjustment disorders as a stress-response disorder with positively defined core symptoms. Objective: This paper provides an overview of evidence-based interventions for adjustment disorders. Methods: We reviewed the new ICD-11 concept of adjustment disorder and discuss the the rationale and case study of an unguided self-help protocol for burglary victims with adjustment disorder, and its possible implementation as an eHealth intervention. Results: Overall, the treatment with the self-help manual reduced symptoms of adjustment disorder, namely preoccupation and failure to adapt, as well as symptoms of depression, anxiety, and stress. Conclusions: E-mental health options are considered uniquely suited for offering early intervention after the experiences of stressful life events that potentially trigger adjustment disorders.

Hepatitis B Infection, Viral Load and Resistance in HIV-Infected Patients in Mozambique and Zambia.

BACKGROUND Few data on the virological determinants of hepatitis B virus (HBV) infection are available from southern Africa. METHODS We enrolled consecutive HIV-infected adult patients initiating antiretroviral therapy (ART) at two urban clinics in Zambia and four rural clinics in Northern Mozambique between May 2013 and August 2014. HBsAg screening was performed using the Determine® rapid test. Quantitative real-time PCR and HBV sequencing were performed in HBsAg-positive patients. Risk factors for HBV infection were evaluated using Chi-square and Mann-Whitney tests and associations between baseline characteristics and high level HBV replication explored in multivariable logistic regression. RESULTS Seventy-eight of 1,032 participants in Mozambique (7.6%, 95% confidence interval [CI]: 6.1-9.3) and 90 of 797 in Zambia (11.3%, 95% CI: 9.3-13.4) were HBsAg-positive. HBsAg-positive individuals were less likely to be female compared to HBsAg-negative ones (52.3% vs. 66.1%, p<0.001). Among 156 (92.9%) HBsAg-positive patients with an available measurement, median HBV viral load was 13,645 IU/mL (interquartile range: 192-8,617,488 IU/mL) and 77 (49.4%) had high values (>20,000 UI/mL). HBsAg-positive individuals had higher levels of ALT and AST compared to HBsAg-negative ones (both p<0.001). In multivariable analyses, male sex (adjusted odds ratio: 2.59, 95% CI: 1.22-5.53) and CD4 cell count below 200/μl (2.58, 1.20-5.54) were associated with high HBV DNA. HBV genotypes A1 (58.8%) and E (38.2%) were most prevalent. Four patients had probable resistance to lamivudine and/or entecavir. CONCLUSION One half of HBsAg-positive patients demonstrated high HBV viremia, supporting the early initiation of tenofovir-containing ART in HIV/HBV-coinfected adults.

Chemical Composition of Micrometer-Sized Filaments in an Aragonite Host by a Miniature Laser Ablation/Ionization Mass Spectrometer

Detection of extraterrestrial life is an ongoing goal in space exploration, and there is a need for advanced instruments and methods for the detection of signatures of life based on chemical and isotopic composition. Here, we present the first investigation of chemical composition of putative microfossils in natural samples using a miniature laser ablation/ionization time-of-flight mass spectrometer (LMS). The studies were conducted with high lateral (similar to 15 mu m) and vertical (similar to 20-200 nm) resolution. The primary aim of the study was to investigate the instrument performance on micrometer-sized samples both in terms of isotope abundance and element composition. The following objectives had to be achieved: (1) Consider the detection and calculation of single stable isotope ratios in natural rock samples with techniques compatible with their employment of space instrumentation for biomarker detection in future planetary missions. (2) Achieve a highly accurate chemical compositional map of rock samples with embedded structures at the micrometer scale in which the rock matrix is easily distinguished from the micrometer structures. Our results indicate that chemical mapping of strongly heterogeneous rock samples can be obtained with a high accuracy, whereas the requirements for isotope ratios need to be improved to reach sufficiently large signal-to-noise ratio (SNR). Key Words: Biogenicity-Biomarkers-Biosignatures-Filaments-Fossilization. Astrobiology 15, 669-682.